Novel benzopyran derivatives

ABSTRACT

WHEREIN R is lower-alkyl are useful as intermediates in the production of steroids, e.g., 4,9(10)-estradiene-3,17-dione.   Benzopyrans of the formula

United States Patent 1 Erler et al.

[ 1 Mar. 27, 1973 [54] NOVEL BENZOPYRAN DERIVATIVES [75] Inventors:Ulrich Eder; Gerhard Sauer, both of Berlin, Germany [73] Assignee:Schering Aktiengesellschaft, Berlin,

Germany [22] Filed: Feb. 4, 1971 [21] Appl. No.: 112,764

[30] Foreign Application Priority Data FOREIGN PATENTS OR APPLICATIONS97,827 1/1964 Denmark ..260/345.2

Primary Examiner-John M. Ford Att0rneyMillen, Raptes & White [57]ABSTRACT Benzopyrans of the formula wherein R is lower-alkyl are usefulas intermediates in the production of steroids, e.g., 4,9(l0)-estradiene- 3,17-dione.

8 Claims, No Drawings NOVEL BENZOPYRAN DERIVATIVES BACKGROUND OF THEINVENTION This invention relates to novel benzopyrans and to a processfor their production.

SUMMARY OF THE INVENTION The compounds of this invention have theformula wherein R is lower-alkyl, and to a process for the preparationof these compounds, wherein an alkyl vinyl ketone of the formulaRCOCI'I=CI-I (II) wherein R has the value given above is condensed inthe absence of a condensation catalyst in the aqueous phase, withcyclohexane-l,3-dione, to produce 2-(3-oxo-alkyl)-cycIohexane-l,3-diones of the formula III wherein R has the value givenabove, and the thusproduced 2-(3-oxoalkyl)-cyclohexane-l,3-dione is thenselectively reduced with keto reducing agent. The reaction mixture isthen worked up in the usual manner, preferably after acidification.

DETAILED DISCUSSION R in the above compounds contains one to six'carbonatoms, e.g., methyl, ethyl, propyl, butyl. Preferred are those wherein Ris methyl or ethyl.

The process of this invention is a two-stage process. In the firststage, lower-alkyl vinyl ketone is condensed with cyclohexane-l ,3-dione. This addition reaction per se is known. However, according toconventional methods, the reaction is conducted in the presence of abasic catalyst. Thus, LN. Nazarov and 8.1. Zavyalor (Isvest. Ak'd. NaukSSSR, Otdel. Khim. Nauk 1957, 207; CA. 51, 1957, 11302 a) describe thereaction of methylvinyl ketone with cyclohexane-l,3-dione in an alkalinesolution. In this reaction, the main reaction product is2,2-bis(3-oxobutyl)-cyclohexane-l,3-dione, whereas the desired product,viz., 2-(3-oxobutyl)- cyclohexane-1,3-dione is isolated in a yield ofonly about 30 percent.

It has now been found that a high yield of the desired2-(3-oxo-alkyl)-cyclohexane-l ,3-dione can be obtained by thecondensation of alkyl vinyl ketones with 1,3-cyclohexanedione in theaqueous phase in the absence of a reaction catalyst. The process of thisinvention produces the desired 2-(3oxo-alkyl)-eyclohexane-l,3-dione inpractically quantitative yield. Thus, expensive purification procedures,which are necessary, for example, in the process described by I.N.Nazarov et al., supra, are avoided.

This smooth, advantageous progression of the first reaction stage of theprocess of this invention is surprising because one skilled in the artknows that the addition of vinyl ketones to 1,3-diketones takes place insuch a manner that the methylene group of the 1,3- diketone forms acarbanion in the presence of bases. Then, the positively chargedterminal methylene group of the vinyl ketone is added to this carbanion.Thus, it could not be expected that the alkyl vinyl ketones would add tocyclohexane-l,3-dione in the absence of basic catalysts. Still lessprobable was the fact that the yield of2-(3-oxoalkyl)-cyclohexane-l,3-dione would be about trebled.

In order to add the alkyl vinyl ketone to cyclohexane-l,3-dione, bothcomponents can be dissolved in water, the solution stored at roomtemperature for about 5-30 hours, and the reaction mixture worked up inthe usual manner, e.g., by extracting the aqueous phase with an organicsolvent, e.g., chloroform, and concentrating the organic phase undervacuum. Substantially pure 2-(3-oxoalkyl)-cyclohexane-l ,3-dione isobtained as the distillation residue.

This simple method of preparation can, of course, also be varied, e.g.,by conducting the reaction at an elevated temperature, but preferablynot substantially above 60 C.; by adding a polar solvent to the reactionmixture, e.g., methanol or acetone, as a solubilizer; and by conductingthe reaction in the absence of atmospheric oxygen so as to avoidundesired side reactions, for example, by storing the reaction mixtureunder an inert gas atmosphere, e.g., nitrogen.

The second stage of the process of this invention is the reduction ofthe thus-produced 2-(3-oxoalkyl)- cyclohexane-l,3-diones. Nothing hasbeen known heretofore about this reduction. Since these compoundscontain three keto groups, it would be expected that the reduction stepwould yield mixtures of various possible partial reduction productsand/or the corresponding trihydroxy compound.

Surprisingly, this is not the case. Instead,2-(3-oxo-alkyl)-c.yclohexane-l,3-diones can be selectively reduced tothe corresponding 2-(3-hydroxyalkyl)- cyclohexane-l ,3-diones, withreducing agents customarily employed for the reduction of keto groups.The thus-formed 2-(3-hydroxyalkyl)-cyclohexane-1,3- diones then aredirectly rearranged, in the presence of acids, into the benzopyranderivatives of Formula I.

Examples of suitable reducing agents which can be employed for theselective reduction of 2-(3-oxoalkyl)- cyclohexane-l,3-diones arehydrogen in the presence of ordinary metal catalysts, e.g., Raneynickel, platinum oxide, or palladium catalysts, as well as theconventional metal hydrides, e.g., sodium borohydride and lithiumaluminum hydride.

The reduction is preferably conducted in an alkaline solution, e.g., anaqueous or alcoholic solution of sodi- V um. hydroxide.

preparing the benzopyran derivative of Formula I in an almostquantitative yield is the reduction of a 2-(3-oxoalkyl)-cyclohexane-l,3-dione with sodium borohydride at 20 to +50 C.

Under these preferred conditions only the keto group of the side chaincan be reduced, whereas the keto groups of the cyclohexane ring are notattacked. Therefor, an almost quantitative yield of the benzopyranderivatives of Formula I can be produced, even if the reduction iscarried out with a large excess of the reducing agent hydrogen or sodiumborohydride.

It is, of course, also possible to employ other metal hydrides in thereduction step, e.g., lithium aluminum hydride; however, these processesare more complicated and expensive than the reduction methodsillustrated in examples herein.

The benzopyrans of Formula I are valuable intermediates for thesynthesis of pharmacologically effective substances, especially steriodhormones of the androstane and pregnane series, especially the19-nor-steroids.

As an example of the use of benzopyran derivatives of Formula I,described below is the synthesis of 4,9(l)-estradiene-3,l7-dione, whichcompound is an important key substance for the preparation of numerouspharmacologically active steroids, e.g., estrone, estradiol, equilin,testosterone, l7a-ethynyl-l9-nortestosterone, etc. This compound can beprepared in a simple manner as follows:

2-Methyl-2,3,4,6,7,8-hexahydro-(5H)-benzopyran- 5-one is converted, witha vinyl magnesium halide, into5-hydroxy-2-methyl-5-vinyl-2,3,4,6,7,8-hexahydro- (5)-benzopyran, which,after the addition of 2-methylcyclopentane-l,3-dione and subsequent acidtreatment, yields 3-methyl-4-oxa-5(l0)8,l4-estratrien-l7- one. Thiscompound is converted, by hydrogenation of the A-double bond andsubsequent isomerization of the A -double bond with acid, into3-methyl-4-oxa-5 (l0),9-estradien-l7-one, which is converted, by chromicacid oxidation in an acidic solution, into 4,5- seco-9(l0)-estrene-3,5,l7-trione. This seco compound is cyclized with acid toproduce 4,9(10)-estradiene- 3,17-dione.

If, in place of Z-methyl-cyclopentane-l,3-dione, 2-ethyl-l,3-cyclopentanedione is employed, the homologous steroids bearinga 4-methyl group are obtained by employing the same method of synthesis.

Thus, reacting ethyl vinyl ketone with 1,3-cyclohexanedione produces2-(3-oxo-n-pentyl)-l,3-cyclohexane-l ,3-dione (Formula I, R C,H.) whichis reduced with sodium borohydride to2-ethyl-2,3,4,6,7,8-hexahydro-(SH)-benzopyran-5-one. This compound isconverted with a vinyl magnesium halide into 5-hydroxy-2-ethyl-5-vinyl-2,3,4,6,7,8-hexahydro-(5)- benzopyran which isalso converted, in the manner described above into4-methyl-4,9(10)-estradiene- 3,17-dione.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitstive ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1 2-(3-Oxobutyl) cyclohexane-1,3-dione Two hundred and fifty g.of resorcinol is hydrogenated to cyclohexane-l ,3-dione in accordancewith the literature (Org. Synth. Coll. Vol. Ill, p.278 [1955]) and thendissolved in 2,400 cc. of water. To this reaction solution is added 225ml. of methyl vinyl ketone in 1,000 ml. of water and the clear solutionis allowed to stand for 24 hours at room temperature under nitrogen. Inorder to remove the excess methyl vinyl ketone, the solution is agitatedunder vacuum at 3040 C., then saturated with sodium chloride, extractedwith chloroform, and the organic phase is dried with sodium sulfate.After the solvent has been distilled off under vacuum, an oil isobtained in a quantitative yield; this oil is readily crystallized and,after recrystallization from ether, yields2-(3-oxobutyl)-cyclohexane-l,3- dione, melting point -104 C.

EXAMPLE 2 2-Methyl-2,3,4,6,7,8-hexahydro[5H]-benzopyran-5- one (a)Reduction with Sodium Borohydride A solution of 4.2 g. of crude2-(3-oxobutyl)- cyclohexane-l,3-dione in 80 ml. of methanol and 20 ml.of 1N sodium hydroxide is cooled to lO C. and mixed batchwise with 0.4g. of sodium borohydride within one hour. Thereafter, the reactionmixture is agitated for one hour at lO C. and for 1 hour at roomtemperature. Then, the mixture is gradually acidified to a pH of 5-6with glacial acetic acid under cooling; then the solvent is extensivelydistilled off under vacuum, and, after the reaction mixture has beentaken up in water, a pH of l-2 is produced with concentratedhydrochloric acid. The solution is saturated with sodium chloride,shaken out with chloroform, and the organic phase is washed withsolution of bicarbonate and water. After drying with sodium sulfate anddistilling off the solvent under vacuum, a crude product is obtainedyielding, after being distilled once under vacuum, 3.5 g. of purecrystalline 2-methyl-2,3,4,6,7,8- hexahydro-[5H]-benzopyran-5-one, m.p.29-30 C.

(b) Reduction by Catalytic Hydrogenation Three hundred and thirty g. ofcrude 2-(3-oxobutyl)- cyclohexane-l,3-dione (produced in accordance withExample 1) is dissolved in 750 ml. of 10 percent sodium hydroxidesolution, and the solution is hydrogenated in the presence of 75 g. ofRaney nickel at 46 C. and atmospheres gauge. After 4 hours, theabsorption of hydrogen is practically complete.

However, the reaction mixture is stirred for another 4 hours under theabove-mentioned conditions. After separating the catalyst, the reactionsolution is mixed with concentrated hydrochloric acid until a pH of 1-2is reached, saturated with sodium chloride, and extracted withchloroform. The organic phase is washed with bicarbonate solution andwater, dried with sodium sulfate, and evaporated. After distilling undervacuum, 290 g. of 2-methyl-2,3,4,6,7,8 -hexahydro-[5H]- benzopyran-S-oneis obtained, which compound is produced in the pure form andcrystallizes when allowed to stand; m.p. 29-30 C. EXAMPLE 3 Convertingof 2-methyl-2,3,4,6,7,8-hexahydro-(5H)- benzopyran-S-one to4,9(l0)-estradiene-3,17-dione and to estrone A solution of 40 g2-methyl-2,3,4,6,7,8-hexahydro- (5H)-benzopyran-5 -one in 200 ml oftetrahydrofuran is added to a vinyl magnesium chloride solution(obtained from 24 g magnesium turnings, 150 ml of tetrahydrofuran andvinyl chloride), which is cooled to -30 C.Thereafter, the reactionmixture is agitated for 30 minutes and than worked up in the usualmanner.

The S-hydroxy-Z-methyl-S-vinyl-2,3,4,6,7-hexahydro-(5H)-benzopryanobtained is dissolved without purification in 200 ml of toluene and thanadded to a boiling mixture of 28 g 2-methylcyclopentane-l,3- dione in1,000 ml toluene. The mixture is boiled for minutes and than worked upin the usual manner. There will be obtained 42 g of 3-methyl-4-oxa-8,l4-seco-5(l0),9(ll)-estradiene-l4,l7-dione of the melting point 72-73C(after recrystallization from methanol).

The seco compound obtained is dissolved in 500 ml of benzene, mgp-toluene sulfonic acid are added and the mixture boiled at a waterseparator for l5 minutes. 0.5 g of palladium calcium carbonate catalystis added to the cooled mixture and the mixture is hydrogenated with thetheoretical amount of hydrogen under normal pressure. Then, the catalystis filtered off, the solution is evaporated under vacuum and the residueis subjected to chromatography on silica gel.

The 3-methyl-4-oxa-5( l0),9(l l )-estradiene-l7-one such obtained isdissolved in 150 ml of dioxane, 15 ml of 2 n sulfuric acid are added andthe mixture is refluxed. After complete reaction the mixture is pooredinto water, extracted with chloroform and the chloroform solutionevaporated under vacuum to dryness. The crude residue is dissolved in100 ml of acetone, ml of Jones reagent (that is 8 11 solution of chromicacid in aquous sulfuric acid) are added and the mixture reacted forminutes. Thenthe mixture is poured into water, extracted with chloroformand the chloroform solution is concentrated under vacuum.

The 4,5-seco-9(10)-estrene-3,5,l7-trione such obtained is dissolved in75 ml of ethanol, 7.5 ml of 4 n sulfuric acid are added, the mixture isrefluxed for one hour and than worked up in the usual manner.

The 4,9(10)-estradiene-3,l7-dione such obtained is dissolved in 100 mlof methanol, 500 mg of palladium magnesium oxide catalyst are added andthe mixture is refluxed for 3 hours. The catalyst is filtered off, thesolution is concentrated under vacuum and the residue obtained isrecrystallized from methanol. There are thus obtained 10.3 g estrone ofthe melting point 245-247C.

The preceding examples can be repeated with similar success bysubstituting the generically of specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

l. A benzopyran of the formula wherein R is lower-alkyl.

2. A compound of claim 1,2-methyl-2,3,4,6,7,8-hexahydro-[5H]-benzopyran-5-one.

3. A process for the production of a benzopyran according to claim 1which comprises the steps of condensing an alkyl vinyl ketone of theformula RCOCH=CH wherein R is lower-alkyl, with cyclohexane-l,3-dione inthe aqueous phase in the absence of a reaction catalyst, to produce a2-(3-oxo-alkyl)- cyclohexane-1,3-dione of the formula 0 II a CHzCHzC-Rwherein R is lowenalkyl, and selectively reducing the thus-produced2-(3-oxoalkyl)-cyclohexane-l,3-dione to produce a2-lower-alkyl-2,3,4,6,7,8-hexahydro-[ 5l-l]-benzopyran-5-one.

4. A process according to claim 3 wherein the reduction is conductedwith hydrogen in the presence of a metal hydrogenation catalyst.

5. A process according to claim 4 wherein the metal catalyst is Raneynickel.

6. A process according to claim 3 wherein the reduction is conductedwith a metal hydride.

7. A process according to claim 6 wherein the metal hydride is sodiumborohydride.

8. A process according to claim 3 wherein the reduction is conducted inan alkaline solution.

1F 1B i

2. A compound of claim 1,2-methyl-2,3,4,6,7,8-hexahydro-(5H)-benzopyran-5-one.
 3. A process forthe production of a benzopyran according to claim 1 which comprises thesteps of condensing an alkyl vinyl ketone of the formula RCOCH CH2wherein R is lower-alkyl, with cyclohexane-1,3-dione in the aqueousphase in the absence of a reaction catalyst, to produce a2-(3-oxo-alkyl)-cyclohexane-1,3-dione of the formula
 4. A processaccording to claim 3 wherein the reduction is conducted with hydrogen inthe presence of a metal hydrogenation catalyst.
 5. A process accordingto claim 4 wherein the metal catalyst is Raney nickel.
 6. A processaccording to claim 3 wherein the reduction is conducted with a metalhydride.
 7. A process according to claim 6 wherein the metal hydride issodium borohydride.
 8. A process according to claim 3 wherein thereduction is conducted in an alkaline solution.